The Effect of  N-Glycosylation of SARS COV-2 Spike Protein on the Virus Interaction With the Host Cell ACE2 Receptor

Human placenta formation relies on the interaction between fused trophoblast cells of the embryo with uterine endometrium. The fusion between trophoblast cells, first into cytotrophoblast and then into syncytiotrophoblast, is facilitated by the fusogenic protein syncytin. Syncytin derives from an envelope glycoprotein (ENV) of retroviral origin. In exogenous retroviruses, the envelope glycoproteins coded by env genes allow fusion of the viral envelope with the host cell membrane and entry of the virus into a host cell. During mammalian evolution, the env genes have been repeatedly, and independently, captured by various mammalian species to facilitate the formation of the placenta. Such a shift in the function of a gene, or a trait, for a different purpose during evolution is called an exaptation (co-option). We discuss the structure and origin of the placenta, the fusogenic and non-fusogenic functions of syncytin, and the mechanism of cell fusion. We also comment on an alleged danger of the COVID-19 vaccine based on the presupposed similarity between syncytin and the SARS-CoV-2 spike protein.

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Role of Structural and Non-Structural Proteins and Therapeutic Targets of SARS-CoV-2 for COVID-19

Cells ◽

10.3390/cells10040821 ◽

2021 ◽

Vol 10 (4) ◽

pp. 821

Author(s):

Rohitash Yadav ◽

Jitendra Kumar Chaudhary ◽

Neeraj Jain ◽

Pankaj Kumar Chaudhary ◽

Supriya Khanra ◽

...

Keyword(s):

Host Cell ◽

Protein S ◽

Structural Similarity ◽

Cell Receptor ◽

Molecular Assembly ◽

The Body ◽

Spike Protein ◽

Structural Proteins ◽

Structural Protein ◽

Novel Coronavirus

Coronavirus belongs to the family of Coronaviridae, comprising single-stranded, positive-sense RNA genome (+ ssRNA) of around 26 to 32 kilobases, and has been known to cause infection to a myriad of mammalian hosts, such as humans, cats, bats, civets, dogs, and camels with varied consequences in terms of death and debilitation. Strikingly, novel coronavirus (2019-nCoV), later renamed as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), and found to be the causative agent of coronavirus disease-19 (COVID-19), shows 88% of sequence identity with bat-SL-CoVZC45 and bat-SL-CoVZXC21, 79% with SARS-CoV and 50% with MERS-CoV, respectively. Despite key amino acid residual variability, there is an incredible structural similarity between the receptor binding domain (RBD) of spike protein (S) of SARS-CoV-2 and SARS-CoV. During infection, spike protein of SARS-CoV-2 compared to SARS-CoV displays 10–20 times greater affinity for its cognate host cell receptor, angiotensin-converting enzyme 2 (ACE2), leading proteolytic cleavage of S protein by transmembrane protease serine 2 (TMPRSS2). Following cellular entry, the ORF-1a and ORF-1ab, located downstream to 5′ end of + ssRNA genome, undergo translation, thereby forming two large polyproteins, pp1a and pp1ab. These polyproteins, following protease-induced cleavage and molecular assembly, form functional viral RNA polymerase, also referred to as replicase. Thereafter, uninterrupted orchestrated replication-transcription molecular events lead to the synthesis of multiple nested sets of subgenomic mRNAs (sgRNAs), which are finally translated to several structural and accessory proteins participating in structure formation and various molecular functions of virus, respectively. These multiple structural proteins assemble and encapsulate genomic RNA (gRNA), resulting in numerous viral progenies, which eventually exit the host cell, and spread infection to rest of the body. In this review, we primarily focus on genomic organization, structural and non-structural protein components, and potential prospective molecular targets for development of therapeutic drugs, convalescent plasm therapy, and a myriad of potential vaccines to tackle SARS-CoV-2 infection.

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Heparan Sulfate Facilitates Spike Protein-Mediated SARS-CoV-2 Host Cell Invasion and Contributes to Increased Infection of SARS-CoV-2 G614 Mutant and in Lung Cancer

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.649575 ◽

2021 ◽

Vol 8 ◽

Author(s):

Jingwen Yue ◽

Weihua Jin ◽

Hua Yang ◽

John Faulkner ◽

Xuehong Song ◽

...

Keyword(s):

Lung Cancer ◽

Cell Surface ◽

Heparan Sulfate ◽

Host Cell ◽

Host Cells ◽

Cell Surface Receptor ◽

Spike Protein ◽

Effective Prevention ◽

Heparin Derivatives ◽

Host Cell Surface

The severe acute respiratory syndrome (SARS)-like coronavirus disease (COVID-19) is caused by SARS-CoV-2 and has been a serious threat to global public health with limited treatment. Cellular heparan sulfate (HS) has been found to bind SARS-CoV-2 spike protein (SV2-S) and co-operate with cell surface receptor angiotensin-converting enzyme 2 (ACE2) to mediate SARS-CoV-2 infection of host cells. In this study, we determined that host cell surface SV2-S binding depends on and correlates with host cell surface HS expression. This binding is required for SARS-Cov-2 virus to infect host cells and can be blocked by heparin lyase, HS antagonist surfen, heparin, and heparin derivatives. The binding of heparin/HS to SV2-S is mainly determined by its overall sulfation with potential, minor contribution of specific SV2-S binding motifs. The higher binding affinity of SV2-S G614 mutant to heparin and upregulated HS expression may be one of the mechanisms underlying the higher infectivity of the SARS-CoV-2 G614 variant and the high vulnerability of lung cancer patients to SARS-CoV-2 infection, respectively. The higher host cell infection by SARS-CoV-2 G614 variant pseudovirus and the increased infection caused by upregulated HS expression both can be effectively blocked by heparin lyase and heparin, and possibly surfen and heparin derivatives too. Our findings support blocking HS-SV2-S interaction may provide one addition to achieve effective prevention and/treatment of COVID-19.

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The effect of N-glycosylation of SARS-CoV-2 spike protein on the virus interaction with the host cell ACE2 receptor

iScience ◽

10.1016/j.isci.2021.103272 ◽

2021 ◽

pp. 103272

Author(s):

Chuncui Huang ◽

Zeshun Tan ◽

Keli Zhao ◽

Wenjun Zou ◽

Hui Wang ◽

...

Keyword(s):

Host Cell ◽

Spike Protein ◽

Virus Interaction

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A modular molecular framework for quickly estimating the binding affinity of the spike protein of SARS-CoV-2 variants for ACE2, in presence of mutations at the spike receptor binding domain.

10.1101/2021.05.26.445422 ◽

2021 ◽

Author(s):

Vincenzo Tragni ◽

Francesca Preziusi ◽

Luna Laera ◽

Angelo Onofrio ◽

Simona Todisco ◽

...

Keyword(s):

Host Cell ◽

Receptor Binding ◽

Conformational Changes ◽

Binding Domain ◽

Host Cells ◽

Spike Protein ◽

Binding Affinities ◽

Receptor Binding Domain ◽

Rapid Spread ◽

Related Proteins

The rapid spread of new SARS-CoV-2 variants needs the development of rapid tools for predicting the affinity of the mutated proteins responsible for the infection, i.e., the SARS-CoV-2 spike protein, for the human ACE2 receptor, aiming to understand if a variant can be more efficient in invading host cells. Here we show how our computational pipeline, previously used for studying SARS-CoV-2 spike receptor-binding domain (RBD)/ACE2 interactions and pre-/post-fusion conformational changes, can be used for predicting binding affinities of the human ACE2 receptor for the spike protein RBD of the characterized infectious variants of concern/interest B.1.1.7-UK (carrying the mutations N501Y, S494P, E484K at the RBD), P.1-Japan/Brazil (RBD mutations: K417N/T, E484K, N501Y), B.1.351-South Africa (RBD mutations: K417N, E484K, N501Y), B.1.427/B.1.429-California (RBD mutations: L452R), the B.1.141 variant (RBD mutations: N439K), and the recent B.1.617.1-India (RBD mutations: L452R; E484Q) and the B.1.620 (RBD mutations: S477N; E484K). Furthermore, we searched for ACE2 structurally related proteins that might be involved in interactions with the SARS-CoV-2 spike protein, in those tissues showing low ACE2 expression, revealing two new proteins, THOP1 and NLN, deserving to be investigated for their possible inclusion in the group of host-cell entry factors responsible for host-cell SARS-CoV-2 invasion and immunity response.

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Mutations in Spike Protein of SARS-CoV-2 Modulate Receptor Binding, Membrane Fusion and Immunogenicity: An Insight into Viral Tropism and Pathogenesis of COVID-19

10.26434/chemrxiv.12320567.v1 ◽

2020 ◽

Cited By ~ 1

Author(s):

Dr. Priyanka Saha ◽

Ranabir Majumder ◽

sourabrata chakraborty ◽

Amit Kumar Srivastava ◽

Mahitosh Mandal ◽

...

Keyword(s):

Host Cell ◽

Cell Entry ◽

Spike Protein ◽

Antigenic Determinants ◽

Chimeric Antibody ◽

Radius Of Gyration ◽

S Protein ◽

Viral Tropism ◽

Host Cell Entry ◽

High Degree

SARS-CoV-2 uses RBD of Spike (S) protein to attach with human cell via ACE2 receptor, followed by protease priming at S1/S2 site resulted in host cell entry and pathogenesis. In this context, we focused our aim in studying natural mutations harboring in Spike protein of SARS-CoV-2. We have analyzed 420 COVID-19 cases. G476S and V483G mutation are observed which lies in the RBD region where as the prevalent D614G mutation is observed in the vicinity of S1/S2 site. Interestingly MD simulation supports strong favorable interaction of ACE2 with RBD region containing V483A mutation as compared to G476S and reference wild Wuhan S protein. Radius of gyration analysis also showed high degree of compactness in V483A. The landscape plot and Gibbs free energy also support our findings. Overall, our study indicates that V483G in the RBD region can enhance its binding with the human ACE2 receptor. Interestingly D614G mutation in vicinity of S1/S2 region introduced a new cleavage site specific for a serine protease elastase that is anticipated to broaden the virus host cell tropism. Hence, both V483A and D614G mutations led to enhanced and broaden the virus host cell entry and transmission of the disease. Further epitope mapping analysis revealed G476S and D614G mutations as antigenic determinants and thus these mutations are important while designing a therapeutics vaccine or chimeric antibody. This finding will help in further understanding the role of such arising mutations in modulating immunogenicity, viral tropism and pathogenesis of the disease, which in lieu will help in designing vaccine more precisely to mitigate pandemic COVID-19.

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Host-cell recognition through GRP78 is enhanced in the new UK variant of SARS-CoV-2, in silico

10.21203/rs.3.rs-147971/v1 ◽

2021 ◽

Author(s):

Abdo A Elfiky ◽

Ibrahim M Ibrahim

Keyword(s):

Host Cell ◽

Cell Receptor ◽

Spike Protein ◽

Cell Recognition ◽

Receptor Binding Domain ◽

Host Cell Receptor ◽

Mutant Variant ◽

New Variant ◽

The Uk ◽

Host Cell Recognition

Abstract New SARS-CoV-2 variant VUI 202012/01 started in the UK and currently spreading in Europe and Australia during the last few days. The new variant bears about nine mutations in the spike protein (Δ69-70, Δ145, N501Y, A570D, D614G, P681H, T716I, S982A, and D1118H). The N501Y lies in the receptor-binding domain (RBD) of the spike and interacts with the host-cell receptor ACE2 responsible for viral recognition and entry. We tried to simulate the system of ACE2-SARS-CoV-2 spike RBD in the wildtype and mutated isoform of the RBD (N501Y). Additionally, the GRP78 association with the ACE2-SARS-CoV-2 spike RBD is modeled at the presence of this mutant variant of the viral spike.

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Elucidating Interactions Between SARS-CoV-2 Trimeric Spike Protein and ACE2 Using Homology Modeling and Molecular Dynamics Simulations

Frontiers in Chemistry ◽

10.3389/fchem.2020.622632 ◽

2021 ◽

Vol 8 ◽

Author(s):

Sugunadevi Sakkiah ◽

Wenjing Guo ◽

Bohu Pan ◽

Zuowei Ji ◽

Gokhan Yavas ◽

...

Keyword(s):

Molecular Dynamics ◽

Homology Modeling ◽

Molecular Dynamics Simulations ◽

Host Cell ◽

Tertiary Structure ◽

Cell Receptor ◽

Host Cells ◽

Spike Protein ◽

Receptor Protein ◽

Dynamics Simulations

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). As of October 21, 2020, more than 41.4 million confirmed cases and 1.1 million deaths have been reported. Thus, it is immensely important to develop drugs and vaccines to combat COVID-19. The spike protein present on the outer surface of the virion plays a major role in viral infection by binding to receptor proteins present on the outer membrane of host cells, triggering membrane fusion and internalization, which enables release of viral ssRNA into the host cell. Understanding the interactions between the SARS-CoV-2 trimeric spike protein and its host cell receptor protein, angiotensin converting enzyme 2 (ACE2), is important for developing drugs and vaccines to prevent and treat COVID-19. Several crystal structures of partial and mutant SARS-CoV-2 spike proteins have been reported; however, an atomistic structure of the wild-type SARS-CoV-2 trimeric spike protein complexed with ACE2 is not yet available. Therefore, in our study, homology modeling was used to build the trimeric form of the spike protein complexed with human ACE2, followed by all-atom molecular dynamics simulations to elucidate interactions at the interface between the spike protein and ACE2. Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) and in silico alanine scanning were employed to characterize the interacting residues at the interface. Twenty interacting residues in the spike protein were identified that are likely to be responsible for tightly binding to ACE2, of which five residues (Val445, Thr478, Gly485, Phe490, and Ser494) were not reported in the crystal structure of the truncated spike protein receptor binding domain (RBD) complexed with ACE2. These data indicate that the interactions between ACE2 and the tertiary structure of the full-length spike protein trimer are different from those between ACE2 and the truncated monomer of the spike protein RBD. These findings could facilitate the development of drugs and vaccines to prevent SARS-CoV-2 infection and combat COVID-19.

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